Multi-omics characterization of HIV-associated changes in the gut microbiome and host mucosal immunity

HIV相关肠道微生物组和宿主粘膜免疫变化的多组学表征

• 批准号: 10466926
• 负责人: Douglas Kwon
• 金额: $ 84.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10466926
• 关键词: 16S ribosomal RNA sequencing; AIDS/HIV problem; Address; Africa South of the Sahara; African; Bacterial Translocation; Biological Assay; Biology; Boston; CD4 Positive T Lymphocytes; Chronic; Communities; Coupled; Data; Data Analyses; Databases; Diabetes Mellitus; Disease; Disease Progression; Environment; Failure; Feces; Functional disorder; Generations; Genes; Genus staphylococcus; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; Human; Hyperglycemia; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologics; Immunology; Impairment; In Vitro; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Institutes; Intestinal Mucosa; Intestines; Lead; Link; Measures; Mediating; Metabolic; Metagenomics; Microbe; Modeling; Molecular; Mucosal Immunity; Mucous Membrane; Mutation; Obesity; Pathogenesis; Patients; Permeability; Phenotype; Plasma; Population; Process; Publishing; Resolution; Resources; Role; STAT3 gene; Sampling; Science; T-Lymphocyte; Technology; Tissues; Uganda; Universities; Virus Diseases; Work; antiretroviral therapy; bacterial community; base; burden of illness; cohort; commensal microbes; data access; exhaustion; experimental study; geographic difference; gut inflammation; gut microbiome; gut microbiota; human subject; immune activation; immune function; innovation; intestinal epithelium; lentiviral-mediated; metabolomics; metatranscriptomics; microbial; microbial community; microbiome; microbiome alteration; microbiome analysis; microbiome composition; multiple omics; new technology; nonhuman primate; novel; pathobiont; screening; skin microbiome; stem cells

PROJECT SUMMARY The human gut harbors an enormously diverse community of commensal microbes that has co-evolved with humans to assist in critical host metabolic and immune functions. The impact of changes in the microbiome on disease states as diverse as diabetes, obesity, immunodeficiency, and inflammatory bowel disease (IBD) is only now being recognized. Human immunodeficiency virus (HIV) infection has profound effects on the intestinal mucosal environment with a hallmark of infection being a rapid depletion of CD4+ T cells within gut associated lymphoid tissue (GALT) and impairment of intestinal epithelial barrier function. Despite this, our understanding of intestinal microbiota changes occurring with HIV infection and the potential effects of these changes on host immunity and HIV disease progression remains incomplete, particularly in populations in sub-Saharan Africa, where HIV disease burden is greatest. Our prior published work is one of only a few studies to examine HIV- associated changes in the gut microbiome in sub-Saharan Africa. Limitations of published studies of HIV- associated alterations in the gut microbiome include 1) the use of 16S rRNA gene sequencing to identify bacterial taxa abundances but failure to resolve differences at the strain level, 2) lack of deep functional characterization of bacterial communities, 3) characterization of HIV-infected populations in developed regions only, and 4) lack of integration with mechanistic experiments. Our proposal addresses the limitations in the field by 1) using comprehensive culturomic, metagenomic, metatranscriptomics, and metabolomic approaches to fully characterize the gut microbiome at the strain level, 2) assessing its function, 3) integrating studies of a U.S. population along with subjects from sub-Saharan Africa, where HIV burden is greatest and where it is known that baseline gut microbiota differ significantly from those living in developed regions and 4) integrating these analyses with mechanistic studies using in vitro and ex vivo models. Overall, the combination of unique, well- characterized human samples analyzed with cutting-edge assays that combine computational and immunologic approaches is highly innovative and will seek to identify bacterial strains, genes, and molecules that impact HIV disease in the U.S. and sub-Saharan Africa. This work will additionally lead to the generation of a multi-‘omic database that will serve as a resource for the field, including community access to data and bacterial strains isolated from samples analyzed in this project.

项目概要 人类肠道蕴藏着极其多样化的共生微生物群落，它们与微生物共同进化 人类协助关键的宿主代谢和免疫功能。微生物组变化对的影响 糖尿病、肥胖症、免疫缺陷和炎症性肠病 (IBD) 等多种疾病状态只是 现在被认可了。人类免疫缺陷病毒（HIV）感染对肠道产生深远影响 粘膜环境的感染特征是肠道内 CD4+ T 细胞的快速消耗 淋巴组织（GALT）和肠上皮屏障功能受损。尽管如此，我们的理解 HIV 感染引起的肠道微生物群变化以及这些变化对宿主的潜在影响 免疫和艾滋病毒疾病进展仍然不完全，特别是在撒哈拉以南非洲的人群中， 艾滋病毒疾病负担最严重的地方。我们之前发表的工作是少数研究艾滋病毒的研究之一 撒哈拉以南非洲地区肠道微生物组的相关变化。已发表的 HIV 研究的局限性 肠道微生物组的相关改变包括 1) 使用 16S rRNA 基因测序来识别细菌 类群丰度但未能解决菌株水平的差异，2）缺乏深入的功能表征 细菌群落的特征，3) 仅发达地区艾滋病毒感染人群的特征，4) 缺乏 与机械实验的结合。我们的建议通过 1）使用来解决该领域的限制 综合的文化组学、宏基因组学、宏转录组学和代谢组学方法，以充分 在菌株水平上表征肠道微生物组，2) 评估其功能，3) 整合美国的研究 人口以及来自撒哈拉以南非洲的受试者，那里的艾滋病毒负担最重并且是已知的 基线肠道微生物群与生活在发达地区的肠道微生物群显着不同，4）整合这些 使用体外和离体模型进行机械研究分析。总体而言，独特的、良好的组合 通过结合计算和免疫学的尖端检测分析表征的人类样本 该方法具有高度创新性，将寻求识别影响艾滋病毒的细菌菌株、基因和分子 美国和撒哈拉以南非洲地区的疾病。这项工作还将导致多组学的产生 数据库将作为该领域的资源，包括社区获取数据和细菌菌株 从本项目分析的样品中分离出来。